The development of a safe, effective acceptable topical microbicide to prevent the sexual transmission of HIV could play a major role in worldwide reduction of the over 14,000 new HIV infections per day, and potentially save millions of lives. Given that cell-free virus ineffectively crosses the genital epithelium in the absence of lesions, it is likely that HIV hijacks host cells as Trojan horses to cross the normally impermeable genital epithelium. It has been postulated that HIV exploits Langerhans (LC) and dendritic cells (DC) to facilitate its safe passage through the genital epithelium. In this application, we propose to develop compounds that prevent HIV-LC and HIV-DC interactions in vitro (R21 phase) and to test them as topical microbicides in vivo (R33 phase). We demonstrated that HIV uses three specific receptors to mediate its initial contact with vaginal LC and DC. We propose to generate reagents that target each of these receptors. These receptor antagonists will then be tested for their capacities to prevent HIV-LC and -DC interactions. The goal is to identify reagents, which are the most potent at blocking in vitro HIV hijacking of vaginal LC and DC. These LC and DC receptor inhibitors will serve as microbicide candidates for subsequent in vivo studies proposed in the R33 phase. We demonstrated that gp120 mediates the contact between HIV and vaginal LC and DC. We propose to generate reagents, which prevent gp120-LC and -DC interactions. Specifically, we propose to generate soluble reagents that mimic the receptors that HIV exploits to interact with LC and DC. These receptor mimics will serve as decoys to prevent gp120 contact with vaginal LC and DC. The goal is to identify receptor mimics, which are the most potent at blocking in vitro HIV hijacking of vaginal LC and DC. These receptor mimics will serve as microbicide candidates for in vivo studies proposed in the R33 phase. One advantage of using compounds that prevent HIV-LC and -DC interactions is that many sexually transmitted pathogens also exploit LC and DC for host colonization, and thus the ability to block HIV-LC and -DC interactions may have the additional benefit of preventing other sexually transmitted pathogens. This approach may not only provide valuable novel microbicides, but it will also allow us to assess the contribution of LC and DC to HIV transmission.